In 1969, it was reported that 2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-1H-pyrido[4,3-b]indole (compound of Formula I, Dimebolin) and 2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-1H-pyrido[4,3-b]indole dihydrochloride (Dimebon) had antihistamine and antiallergic effects (U.S. Pat. No. 3,484,449). In 1983, it was marketed in the former Soviet Union as an antiallergic agent for clinic use (Farmakologiia i Toksikologiia 46 (4): 27-29); and the protective effects of the compound on nerves and the effects of the compound for improving cognitive dysfunction had been studied (Vestnik Rossiiskoi Akademii Meditsinskikh Nauk (9): 13-17).
In recent years, some studies indicate that Dimebolin has a bioactivity by oral administration. It has been shown that this product inhibits the death of brain cells in pre-clinical trials on Alzheimer's disease and Huntington's disease, can enhance the cognition of healthy people and patients with never degenerative diseases, and can treat cognitive dysfunction syndrome in dogs (US08036400). Studies indicate that Dimebolin has potential therapeutic effects on the abovementioned and other never degenerative diseases (Annals of the New York Academy of Sciences (939): 425-435).
Some researches also show that Dimebolin has a significant therapeutic effect in the patients with Alzheimer's disease. In 2000, a research conducted in an animal model of Alzheimer's disease in Russia indicated that Dimebolin had a significant therapeutic effect on Alzheimer's disease (Bulletin of Experimental Biology and Medicine 129 (6): 544-546). Recently, the results of a phase II human clinical trial for initial 6 months have showed that Dimebolin has a significant effect for improving patients with Alzheimer's disease as compared to the placebo, and a phase III double blind clinical trial is performing now (Antihistamine Shows Promise in Treating Alzheimer's″, New York Times (2007-06-11)).
2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-1H-pyrido-[4,3-b]indole (compound of Formula I) and 2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-1H-pyrido[4,3-b]indole dihydrochloride (Dimebolin, Dimebon) are novel compounds capable of treating never degenerative diseases such as cognitive dysfunction syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, senile dementia, etc., and there are two preparations thereof for human clinical trials, i.e., preparations respectively containing 5 mg and 20 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-1H-pyrido[4,3-b]indole (compound of Formula I), in which the recommended usage of the 20 mg preparation is three times per day, i.e., the activity of the preparation can keep for 8 hours, so that it should be taken three times per day.
However, although Dimebolin is a compound capable of treating never degenerative diseases such as cognitive dysfunction syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, senile dementia, etc., the current preparation that has to be taken three times per day is not favorable for the treatment of patients with never degenerative diseases such as cognitive dysfunction syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, senile dementia, etc., because the patients may hardly remember too many times of drug administration and may very likely forget the administration due to their diseases; and in the meantime, drug administration for several times is also inconvenient for those accompanying and attending the patients.
The object of the present invention is to provide a sustained-release unit dosage form for oral administration comprising 2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-1H-pyrido[4,3-b]indole (compound of Formula I, Dimebolin) or a pharmaceutically acceptable salt thereof as an active ingredient, and the pharmaceutically acceptable salt is most preferably 2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-1H-pyrido[4,3-b]indole dihydrochloride (Dimebon). The dosage form has an effective activity duration of 24 hours or more, and thus is suitable for administration by one time per day, thereby being greatly convenient to patients with never degenerative diseases such as cognitive dysfunction syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, senile dementia, etc. and those accompanying and attending the patients, avoiding weakening therapeutic effect in the patients caused by missing administration, and facilitating the treatment and recovery of the patients.